Abstract
The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.
Highlights
Telomeres and their associated shelterin complex are located at chromosomal ends
In glioblastoma multiforme (GBM), TERT promoter (TERTp) mutations coexist with epidermal growth factor receptor (EGFR) amplification [64,77,111], and in urothelial bladder carcinoma, they are associated with FGFR3 (Fibroblast Growth Factor Receptor 3)
TERTp mutations have only been described recently; they have prompted an impressive number of studies which draw a comprehensive picture of their prevalence across cancers, as well as providing clues on their mechanisms of action and their associated constraints
Summary
Telomeres and their associated shelterin complex are located at chromosomal ends. Telomeres are tandem repeats of TTAGGG up to 15 kb long in humans. Cells 2020, 9, 749 reactivated by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements. Startbetween site (TSS), encompassing thethe core promoter, of specific regions. Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, reactivating exon The region between −600 and −200 frombinding the TSS site and isa partially hypermethylated in TERT-expressing cells [41,42,43,44]. Transcriptional control of contains second CTCF binding site and is partially hypermethylated inThe. TERT-expressing cells has been comprehensively reviewed recently [3,4,9,18,19,20,21,22,29,48].
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